With the development and widespread use of highly active antiretroviral therapy, the survival of individuals infected with HIV-1 has dramatically improved. However, with this increased survival has come the recognition that HIV infection is associated with the accelerated development of chronic disorders usually associated with aging. Among the most common is chronic obstructive pulmonary disease (COPD), primarily in cigarette smokers, with the combination of HIV infection and smoking accelerating the onset and risk for COPD. Why is HIV infection such an important risk factor for COPD in smokers? Based on the knowledge that the small airways are the major site of airflow obstruction in COPD, the first pathologic manifestations of cigarette smoking are in the small airway epithelium (SAE), the emphysema associated with COPD starts in alveoli surrounding the SAE, smoking induces marked disordering of the transcriptome of the SAE, and our evidence that telomeres of SAE of HIV+ smokers are shorter than that of HIV- smokers, we propose that the accelerated development of COPD in smokers with HIV infection results from the premature biologic aging of the SAE, generated by the effects of direct HIV infection of the SAE, and/or through the interaction of HIV-infected T cells and/or alveolar macrophages (AM) with the SAE. We have assembled a study cohort of HIV+ subjects (n=305) and HIV- controls (HIV- nonsmokers, healthy smokers, and smokers with COPD, total n=2,655) and we will evaluate 15-20 newly diagnosed, untreated HIV+ individuals/yr. Together, we have all of the relevant methodologies and infrastructure to carry out the proposed studies articulated in 3 specific aims. Aim 1. In HIV+ smokers who have no clinical evidence of lung disease, we hypothesize that the SAE is aging prematurely; exhibiting biologic disordering that is similar to the disordered biology of the SAE of HIV smokers with COPD. Aim 2. To assess the hypothesis that the accelerated biologic aging of the SAE of the HIV+ smoker results from the interaction of HIV with the SAE directly or indirectly though HIV infected T cells and/or AM. Aim 3. To evaluate the hypothesis that the T cells and/or AMs of HIV+ smokers with tight control of viral loads will no longer be able to mediate the accelerated biologic aging associated with the SAE. Together, these studies will help unravel the pathogenesis of the HIV-associated development of COPD, help identify new targets for pharmacologic intervention and add to the evidence that tight control of HIV infection may be useful in reducing the incidence of HIV-associated COPD.